Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.
INSERM U964, Illkirch 67404, France.
Nat Commun. 2017 Jun 7;8:15661. doi: 10.1038/ncomms15661.
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing. Moreover, systemic ASO injection into severely affected mice leads to reversal of muscle pathology within 2 weeks. Thus, ASO-mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease.
先天性肌营养不良症（CNM）是非营养不良性肌肉疾病，目前尚无有效的治疗方法。最严重的形式，X 连锁先天性肌营养不良症，是由肌小管素 1（MTM1）功能丧失突变引起的，而主要的常染色体显性形式是由于 dynamin2（DNM2）突变引起的。我们之前表明，在 Mtm1 敲除（Mtm1KO）小鼠中降低 DNM2 的表达可预防肌肉病理的发展。在这里，我们表明系统递送到 Mtm1KO 小鼠中的 Dnm2 反义寡核苷酸（ASO）有效地降低了肌肉中的 DNM2 蛋白水平，并防止了肌肉病的发展。此外，系统 ASO 注射到严重受影响的小鼠中可在 2 周内逆转肌肉病理。因此，ASO 介导的 DNM2 敲低可有效地纠正由于 MTM1 缺失引起的肌肉缺陷，为这种疾病提供了一种有吸引力的治疗策略。
